Autophagy promotes cell survival by maintaining NAD levels
Name
1-s2.0-S1534580722007602-main.pdf
Description
Published version
Size
9.99 MB
Format
Adobe PDF
Checksum (MD5)
e0590a9a6b0a2484da9d78cafa9fe51b
Author(s)
Jaenisch, Rudolf
Date Issued
November 2022
Journal
Developmental Cell
Publisher
Elsevier BV
Citation
Jaenisch, Rudolf. 2022. "Autophagy promotes cell survival by maintaining NAD levels." Developmental Cell, 57 (22).
Version
Final published version
Abstract
Autophagy is an essential catabolic process that promotes the clearance of surplus or damaged intracellular components. Loss of autophagy in age-related human pathologies contributes to tissue degeneration through a poorly understood mechanism. Here, we identify an evolutionarily conserved role of autophagy from yeast to humans in the preservation of nicotinamide adenine dinucleotide (NAD) levels, which are critical for cell survival. In respiring mouse fibroblasts with autophagy deficiency, loss of mitochondrial quality control was found to trigger hyperactivation of stress responses mediated by NADases of PARP and Sirtuin families. Uncontrolled depletion of the NAD(H) pool by these enzymes ultimately contributed to mitochondrial membrane depolarization and cell death. Pharmacological and genetic interventions targeting several key elements of this cascade improved the survival of autophagy-deficient yeast, mouse fibroblasts, and human neurons. Our study provides a mechanistic link between autophagy and NAD metabolism and identifies targets for interventions in human diseases associated with autophagic, lysosomal, and mitochondrial dysfunction.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.devcel.2022.10.008
